467 results on '"Loh, P. H."'
Search Results
2. Roles of Baseline Intrinsic Capacity and its Subdomains on the Overall Efficacy of Multidomain Intervention in Promoting Healthy Aging among Community-Dwelling Older Adults: Analysis from a Nationwide Cluster-Randomized Controlled Trial
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Liang, C.-K., Lee, W.-J., Chou, M.-Y., Hwang, A.-C., Lin, C.-S., Peng, L.-N., Hsiao, F.-Y., Loh, C.-H., and Chen, Liang-Kung
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- 2024
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3. Genome-wide CRISPR/Cas9 screen shows that loss of GET4 increases mitochondria-endoplasmic reticulum contact sites and is neuroprotective
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Wilson, Emma L., Yu, Yizhou, Leal, Nuno S., Woodward, James A., Patikas, Nikolaos, Morris, Jordan L., Field, Sarah F., Plumbly, William, Paupe, Vincent, Chowdhury, Suvagata R., Antrobus, Robin, Lindop, Georgina E., Adia, Yusuf M., Loh, Samantha H. Y., Prudent, Julien, Martins, L. Miguel, and Metzakopian, Emmanouil
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- 2024
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4. KeyLoop retractor for global gasless laparoscopy: evaluation of safety and feasibility in a porcine model
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Zadey, Siddhesh, Leraas, Harold, Gupta, Aryaman, Biswas, Arushi, Hollier, Pierce, Vissoci, Joao Ricardo Nickenig, Mugaga, Julius, Ssekitoleko, Robert T., Everitt, Jeffrey I., Loh, Amos H. P., Lee, York Tien, Saterbak, Ann, Mueller, Jenna L., and Fitzgerald, Tamara N.
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- 2023
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5. Evidence for involvement of the alcohol consumption WDPCP gene in lipid metabolism, and liver cirrhosis
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O’Farrell, Felix, Aleyakpo, Benjamin, Mustafa, Rima, Jiang, Xiyun, Pinto, Rui Climaco, Elliott, Paul, Tzoulaki, Ioanna, Dehghan, Abbas, Loh, Samantha H. Y., Barclay, Jeff W., Martins, L. Miguel, and Pazoki, Raha
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- 2023
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6. The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain complex I inhibitors
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Hardy, Rachel E., Chung, Injae, Yu, Yizhou, Loh, Samantha H. Y., Morone, Nobuhiro, Soleilhavoup, Clement, Travaglio, Marco, Serreli, Riccardo, Panman, Lia, Cain, Kelvin, Hirst, Judy, Martins, Luis M., MacFarlane, Marion, and Pryde, Kenneth R.
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- 2023
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7. Long-Term Mortality Risk in Older Adults with Sarcopenia: An 11-Year Prospective Cohort Study Comparing AWGS 2014 and AWGS 2019 Guidelines for Enhanced Clinical Utility and Accurate Risk Prediction
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Liang, C.-K., Peng, L.-N., Lin, M.-H., Loh, C.-H., Lee, Wei-Ju, Hsiao, F.-Y., and Chen, L.-K.
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- 2023
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8. RIXS Reveals Hidden Local Transitions of the Aqueous OH Radical
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Kjellsson, L., Nanda, K., Rubensson, J. -E., Doumy, G., Southworth, S. H., Ho, P. J., March, A. M., Haddad, A. Al, Kumagai, Y., Tu, M. -F., Schaller, R., Debnath, T., Yusof, M. S. Bin Mohd, Arnold, C., Schlotter, W. F., Moeller, S., Coslovich, G., Koralek, J. D., Minitti, M. P., Vidal, M. L., Simon, M., Santra, R., Loh, Z. -H., Coriani, vS., Krylov, A. I., and Young, L.
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Physics - Chemical Physics - Abstract
Resonant inelastic x-ray scattering (RIXS) provides remarkable opportunities to interrogate ultrafast dynamics in liquids. Here we use RIXS to study the fundamentally and practically important hydroxyl radical in liquid water, OH(aq). Impulsive ionization of pure liquid water produced a short-lived population of OH(aq), which was probed using femtosecond x-rays from an x-ray free-electron laser. We find that RIXS reveals localized electronic transitions that are masked in the ultraviolet absorption spectrum by strong charge-transfer transitions -- thus providing a means to investigate the evolving electronic structure and reactivity of the hydroxyl radical in aqueous and heterogeneous environments. First-principles calculations provide interpretation of the main spectral features., Comment: 40 pages, 10 figures
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- 2020
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9. Melatonin treatment of repetitive behavioral deficits in the Cntnap2 mouse model of autism spectrum disorder
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Bin Wang, Huei, Tahara, Yu, Luk, Shu Hon Christopher, Kim, Yoon-Sik, Hitchcock, Olivia N, Kaswan, Zoe A MacDowell, Kim, Yang In, Block, Gene D, Ghiani, Cristina A, Loh, Dawn H, and Colwell, Christopher S
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Biomedical and Clinical Sciences ,Neurosciences ,Genetics ,Behavioral and Social Science ,Basic Behavioral and Social Science ,Brain Disorders ,Autism ,Pediatric ,Intellectual and Developmental Disabilities (IDD) ,Mental Health ,Sleep Research ,2.1 Biological and endogenous factors ,Mental health ,Animals ,Autism Spectrum Disorder ,Behavior ,Animal ,Central Nervous System Depressants ,Circadian Rhythm ,Disease Models ,Animal ,Lighting ,Melatonin ,Membrane Proteins ,Mice ,Mice ,Knockout ,Nerve Tissue Proteins ,Autism spectrum disorder ,Circadian ,Cntnap2 ,Light pollution ,Clinical Sciences ,Neurology & Neurosurgery ,Biochemistry and cell biology - Abstract
Nighttime light pollution is linked to metabolic and cognitive dysfunction. Many patients with autism spectrum disorders (ASD) show disturbances in their sleep/wake cycle, and may be particularly vulnerable to the impact of circadian disruptors. In this study, we examined the impact of exposure to dim light at night (DLaN, 5 lx) in a model of ASD: the contactin associated protein-like 2 knock out (Cntnap2 KO) mice. DLaN was sufficient to disrupt locomotor activity rhythms, exacerbate the excessive grooming and diminish the social preference in Cntnap2 mutant mice. On a molecular level, DLaN altered the phase and amplitude of PER2:LUC rhythms in a tissue-specific manner in vitro. Daily treatment with melatonin reduced the excessive grooming of the mutant mice to wild-type levels and improved activity rhythms. Our findings suggest that common circadian disruptors such as light at night should be considered in the management of ASD.
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- 2020
10. Melatonin treatment of repetitive behavioral deficits in the Cntnap2 mouse model of autism spectrum disorder.
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Wang, Huei Bin, Tahara, Yu, Luk, Shu Hon Christopher, Kim, Yoon-Sik, Hitchcock, Olivia N, MacDowell Kaswan, Zoe A, In Kim, Yang, Block, Gene D, Ghiani, Cristina A, Loh, Dawn H, and Colwell, Christopher S
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Autism spectrum disorder ,Circadian ,Cntnap2 ,Light pollution ,Melatonin ,Mice ,Neurology & Neurosurgery ,Clinical Sciences ,Neurosciences - Abstract
Nighttime light pollution is linked to metabolic and cognitive dysfunction. Many patients with autism spectrum disorders (ASD) show disturbances in their sleep/wake cycle, and may be particularly vulnerable to the impact of circadian disruptors. In this study, we examined the impact of exposure to dim light at night (DLaN, 5 lx) in a model of ASD: the contactin associated protein-like 2 knock out (Cntnap2 KO) mice. DLaN was sufficient to disrupt locomotor activity rhythms, exacerbate the excessive grooming and diminish the social preference in Cntnap2 mutant mice. On a molecular level, DLaN altered the phase and amplitude of PER2:LUC rhythms in a tissue-specific manner in vitro. Daily treatment with melatonin reduced the excessive grooming of the mutant mice to wild-type levels and improved activity rhythms. Our findings suggest that common circadian disruptors such as light at night should be considered in the management of ASD.
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- 2020
11. Disentangling Mortality Associations: An In-depth Comparative Study of Possible Sarcopenia versus Sarcopenia of AWGS 2019
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Lee, W.-J., Peng, L.-N., Lin, M.-H., Loh, C.-H., and Chen, Liang-Kung
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- 2023
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12. Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis.
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Smarr, Benjamin, Cutler, Tamara, Loh, Dawn H, Kudo, Takashi, Kuljis, Dika, Kriegsfeld, Lance, Ghiani, Cristina A, and Colwell, Christopher S
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Huntington's disease ,Q175 ,autonomic nervous system ,cardiovascular function ,circadian rhythms ,phase coherence ,suprachiasmatic nucleus ,Neurosciences ,Psychology ,Neurology & Neurosurgery - Abstract
Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington's disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, have been the topic of a number of recent studies. The (z)Q175 mouse is a knock-in model in which the human exon 1 sequence of the huntingtin gene is inserted into the mouse DNA with approximately 190 CAG repeats. Among the numerous models available, the heterozygous Q175 offers strong construct validity with a single copy of the mutation, genetic precision of the insertion and control of mutation copy number. In this review, we will summarize the evidence that this model exhibits disrupted diurnal and circadian rhythms in locomotor activity. We found overwhelming evidence for autonomic dysfunction including blunted daily rhythms in heart rate and core body temperature (CBT), reduced heart rate variability, and almost a complete failure of the sympathetic arm of the autonomic nervous system to function during the baroreceptor reflex. Mechanistically, the Q175 mouse model exhibits deficits in the neural output of the central circadian clock, the suprachiasmatic nucleus along with an enhancement of at least one type of potassium current in these neurons. Finally, we report a novel network analysis examining the phase coherence between activity, CBT, and cardiovascular measures. Such analyses found that even young Q175 mutants (heterozygous or homozygous) show coherence degradation, and suggests that loss of phase coherence is a variable that should be considered as a possible biomarker for HD.
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- 2019
13. Mitochondrial ROS signalling requires uninterrupted electron flow and is lost during ageing in flies
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Graham, Charlotte, Stefanatos, Rhoda, Yek, Angeline E. H., Spriggs, Ruth V., Loh, Samantha H. Y., Uribe, Alejandro Huerta, Zhang, Tong, Martins, L. Miguel, Maddocks, Oliver D. K., Scialo, Filippo, and Sanz, Alberto
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- 2022
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14. Blocking dPerk in the intestine suppresses neurodegeneration in a Drosophila model of Parkinson’s disease
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Popovic, Rebeka, Mukherjee, Amrita, Leal, Nuno Santos, Morris, Lydia, Yu, Yizhou, Loh, Samantha H. Y., and Miguel Martins, L.
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- 2023
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15. The therapeutic potential of RNA Polymerase I transcription inhibitor, CX-5461, in uterine leiomyosarcoma
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Kang, Chang-Won, Hannan, Katherine M., Blackburn, Anneke C., Loh, Amos H. P., Hong, Kuick Chik, Yuan, Goh Jian, Hein, Nadine, Drygin, Denis, Hannan, Ross D., and Coupland, Lucy A.
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- 2022
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16. High-Performance and Energy-Effcient Memory Scheduler Design for Heterogeneous Systems
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Ausavarungnirun, Rachata, Loh, Gabriel H., Subramanian, Lavanya, Chang, Kevin, and Mutlu, Onur
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Computer Science - Hardware Architecture - Abstract
When multiple processor cores (CPUs) and a GPU integrated together on the same chip share the off-chip DRAM, requests from the GPU can heavily interfere with requests from the CPUs, leading to low system performance and starvation of cores. Unfortunately, state-of-the-art memory scheduling algorithms are ineffective at solving this problem due to the very large amount of GPU memory traffic, unless a very large and costly request buffer is employed to provide these algorithms with enough visibility across the global request stream. Previously-proposed memory controller (MC) designs use a single monolithic structure to perform three main tasks. First, the MC attempts to schedule together requests to the same DRAM row to increase row buffer hit rates. Second, the MC arbitrates among the requesters (CPUs and GPU) to optimize for overall system throughput, average response time, fairness and quality of service. Third, the MC manages the low-level DRAM command scheduling to complete requests while ensuring compliance with all DRAM timing and power constraints. This paper proposes a fundamentally new approach, called the Staged Memory Scheduler (SMS), which decouples the three primary MC tasks into three significantly simpler structures that together improve system performance and fairness. Our evaluation shows that SMS provides 41.2% performance improvement and fairness improvement compared to the best previous state-of-the-art technique, while enabling a design that is significantly less complex and more power-efficient to implement.
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- 2018
17. Holistic Management of the GPGPU Memory Hierarchy to Manage Warp-level Latency Tolerance
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Ausavarungnirun, Rachata, Ghose, Saugata, Kayıran, Onur, Loh, Gabriel H., Das, Chita R., Kandemir, Mahmut T., and Mutlu, Onur
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Computer Science - Hardware Architecture - Abstract
In a modern GPU architecture, all threads within a warp execute the same instruction in lockstep. For a memory instruction, this can lead to memory divergence: the memory requests for some threads are serviced early, while the remaining requests incur long latencies. This divergence stalls the warp, as it cannot execute the next instruction until all requests from the current instruction complete. In this work, we make three new observations. First, GPGPU warps exhibit heterogeneous memory divergence behavior at the shared cache: some warps have most of their requests hit in the cache, while other warps see most of their request miss. Second, a warp retains the same divergence behavior for long periods of execution. Third, requests going to the shared cache can incur queuing delays as large as hundreds of cycles, exacerbating the effects of memory divergence. We propose a set of techniques, collectively called Memory Divergence Correction (MeDiC), that reduce the negative performance impact of memory divergence and cache queuing. MeDiC delivers an average speedup of 21.8%, and 20.1% higher energy efficiency, over a state-of-the-art GPU cache management mechanism across 15 different GPGPU applications.
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- 2018
18. Suppression of intestinal dysfunction in a Drosophila model of Parkinson’s disease is neuroprotective
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Fedele, Giorgio, Loh, Samantha H. Y., Celardo, Ivana, Leal, Nuno Santos, Lehmann, Susann, Costa, Ana C., and Martins, L. Miguel
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- 2022
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19. Mutations of 1p genes do not consistently abrogate tumor suppressor functions in 1p-intact neuroblastoma
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Kuick, Chik Hong, Tan, Jia Ying, Jasmine, Deborah, Sumanty, Tohari, Ng, Alvin Y. J., Venkatesh, Byrrappa, Chen, Huiyi, Loh, Eva, Jain, Sudhanshi, Seow, Wan Yi, Ng, Eileen H. Q., Lian, Derrick W. Q., Soh, Shui Yen, Chang, Kenneth T. E., Chen, Zhi Xiong, and Loh, Amos H. P.
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- 2022
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20. Outdoor public recreation spaces and social connectedness among adolescents
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Rivera, Elise, Veitch, Jenny, Loh, Venurs H. Y., Salmon, Jo, Cerin, Ester, Mavoa, Suzanne, Villanueva, Karen, and Timperio, Anna
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- 2022
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21. CODA: Enabling Co-location of Computation and Data for Near-Data Processing
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Kim, Hyojong, Hadidi, Ramyad, Nai, Lifeng, Kim, Hyesoon, Jayasena, Nuwan, Eckert, Yasuko, Kayiran, Onur, and Loh, Gabriel H.
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Computer Science - Hardware Architecture - Abstract
Recent studies have demonstrated that near-data processing (NDP) is an effective technique for improving performance and energy efficiency of data-intensive workloads. However, leveraging NDP in realistic systems with multiple memory modules introduces a new challenge. In today's systems, where no computation occurs in memory modules, the physical address space is interleaved at a fine granularity among all memory modules to help improve the utilization of processor-memory interfaces by distributing the memory traffic. However, this is at odds with efficient use of NDP, which requires careful placement of data in memory modules such that near-data computations and their exclusively used data can be localized in individual memory modules, while distributing shared data among memory modules to reduce hotspots. In order to address this new challenge, we propose a set of techniques that (1) enable collections of OS pages to either be fine-grain interleaved among memory modules (as is done today) or to be placed contiguously on individual memory modules (as is desirable for NDP private data), and (2) decide whether to localize or distribute each memory object based on its anticipated access pattern and steer computations to the memory where the data they access is located. Our evaluations across a wide range of workloads show that the proposed mechanism improves performance by 31% and reduces 38% remote data accesses over a baseline system that cannot exploit computate-data affinity characteristics., Comment: 14 pages, 16 figures
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- 2017
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22. Stimuli-Responsive Substrates to Control the Immunomodulatory Potential of Stromal Cells.
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Castilla-Casadiego, David A., Loh, Darren H., Pineda-Hernandez, Aldaly, and Rosales, Adrianne M.
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- 2024
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23. Laparoscopic experience and attitudes toward a low-cost laparoscopic system among surgeons in East, Central, and Southern Africa: a survey study
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Farrow, Norma E., Commander, Sarah J., Reed, Christopher R., Mueller, Jenna L., Gupta, Aryaman, Loh, Amos H. P., Sekabira, John, and Fitzgerald, Tamara N.
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- 2021
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24. Time-Restricted Feeding Improves Circadian Dysfunction as well as Motor Symptoms in the Q175 Mouse Model of Huntington's Disease.
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Wang, Huei-Bin, Loh, Dawn H, Whittaker, Daniel S, Cutler, Tamara, Howland, David, and Colwell, Christopher S
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Autonomic Nervous System ,Animals ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Huntington Disease ,Disease Models ,Animal ,Fasting ,Motor Activity ,Sleep ,Circadian Rhythm ,Heart Rate ,Eating ,Time Factors ,Male ,Huntington’s disease ,Q175 ,circadian rhythms ,fast/feed cycle ,time-restricted feeding ,Huntington's disease ,Neurosciences - Abstract
Huntington's disease (HD) patients suffer from a progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep/wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and fatigue during the day. The heterozygous Q175 mouse model of HD has been shown to phenocopy many HD core symptoms including circadian dysfunctions. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early intervention that improve circadian rhythmicity can benefit HD and delay disease progression. We determined the effects of time-restricted feeding (TRF) on the Q175 mouse model. At six months of age, the animals were divided into two groups: ad libitum (ad lib) and TRF. The TRF-treated Q175 mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle of the time when mice are normally active. After three months of treatment (when mice reached the early disease stage), the TRF-treated Q175 mice showed improvements in their locomotor activity rhythm and sleep awakening time. Furthermore, we found improved heart rate variability (HRV), suggesting that their autonomic nervous system dysfunction was improved. Importantly, treated Q175 mice exhibited improved motor performance compared to untreated Q175 controls, and the motor improvements were correlated with improved circadian output. Finally, we found that the expression of several HD-relevant markers was restored to WT levels in the striatum of the treated mice using NanoString gene expression assays.
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- 2018
25. Gastrointestinal and oncologic outcomes of pediatric gastrointestinal lymphoma following upfront resection or biopsy of bowel masses
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Othman, Mohd Yusran, Halepota, Huma Faiz, Le Linn, Yun, Lee, York Tien, Chang, Kenneth T. E., Ahamed, Summaiyya Hanum, Lam, Joyce C. M., Bhattacharyya, Rajat, Tan, Ah Moy, and Loh, Amos H. P.
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- 2021
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26. Achieving both High Energy Efficiency and High Performance in On-Chip Communication using Hierarchical Rings with Deflection Routing
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Ausavarungnirun, Rachata, Fallin, Chris, Yu, Xiangyao, Chang, Kevin Kai-Wei, Nazario, Greg, Das, Reetuparna, Loh, Gabriel H., and Mutlu, Onur
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Computer Science - Distributed, Parallel, and Cluster Computing ,C.1.2 ,B.4.3 - Abstract
Hierarchical ring networks, which hierarchically connect multiple levels of rings, have been proposed in the past to improve the scalability of ring interconnects, but past hierarchical ring designs sacrifice some of the key benefits of rings by introducing more complex in-ring buffering and buffered flow control. Our goal in this paper is to design a new hierarchical ring interconnect that can maintain most of the simplicity of traditional ring designs (no in-ring buffering or buffered flow control) while achieving high scalability as more complex buffered hierarchical ring designs. Our design, called HiRD (Hierarchical Rings with Deflection), includes features that allow us to mostly maintain the simplicity of traditional simple ring topologies while providing higher energy efficiency and scalability. First, HiRD does not have any buffering or buffered flow control within individual rings, and requires only a small amount of buffering between the ring hierarchy levels. When inter-ring buffers are full, our design simply deflects flits so that they circle the ring and try again, which eliminates the need for in-ring buffering. Second, we introduce two simple mechanisms that provides an end-to-end delivery guarantee within the entire network without impacting the critical path or latency of the vast majority of network traffic. HiRD attains equal or better performance at better energy efficiency than multiple versions of both a previous hierarchical ring design and a traditional single ring design. We also analyze our design's characteristics and injection and delivery guarantees. We conclude that HiRD can be a compelling design point that allows higher energy efficiency and scalability while retaining the simplicity and appeal of conventional ring-based designs.
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- 2016
27. Enabling Efficient Dynamic Resizing of Large DRAM Caches via A Hardware Consistent Hashing Mechanism
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Chang, Kevin K., Loh, Gabriel H., Thottethodi, Mithuna, Eckert, Yasuko, O'Connor, Mike, Manne, Srilatha, Hsu, Lisa, Subramanian, Lavanya, and Mutlu, Onur
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Computer Science - Hardware Architecture - Abstract
Die-stacked DRAM has been proposed for use as a large, high-bandwidth, last-level cache with hundreds or thousands of megabytes of capacity. Not all workloads (or phases) can productively utilize this much cache space, however. Unfortunately, the unused (or under-used) cache continues to consume power due to leakage in the peripheral circuitry and periodic DRAM refresh. Dynamically adjusting the available DRAM cache capacity could largely eliminate this energy overhead. However, the current proposed DRAM cache organization introduces new challenges for dynamic cache resizing. The organization differs from a conventional SRAM cache organization because it places entire cache sets and their tags within a single bank to reduce on-chip area and power overhead. Hence, resizing a DRAM cache requires remapping sets from the powered-down banks to active banks. In this paper, we propose CRUNCH (Cache Resizing Using Native Consistent Hashing), a hardware data remapping scheme inspired by consistent hashing, an algorithm originally proposed to uniformly and dynamically distribute Internet traffic across a changing population of web servers. CRUNCH provides a load-balanced remapping of data from the powered-down banks alone to the active banks, without requiring sets from all banks to be remapped, unlike naive schemes to achieve load balancing. CRUNCH remaps only sets from the powered-down banks, so it achieves this load balancing with low bank power-up/down transition latencies. CRUNCH's combination of good load balancing and low transition latencies provides a substrate to enable efficient DRAM cache resizing., Comment: 13 pages
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- 2016
28. Possible use of a H3R antagonist for the management of nonmotor symptoms in the Q175 mouse model of Huntington's disease.
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Whittaker, Daniel S, Wang, Huei-Bin, Loh, Dawn H, Cachope, Roger, and Colwell, Christopher S
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Animals ,Humans ,Mice ,Huntington Disease ,Disease Models ,Animal ,Niacinamide ,Benzazepines ,Receptors ,Histamine H3 ,Drug Administration Schedule ,Motor Activity ,Cognition ,Maze Learning ,Male ,Histamine H3 Antagonists ,Circadian rhythms ,GSK189254 ,Huntington's disease ,histamine ,histamine-3 receptor ,nonmotor symptoms ,sleep behavior ,Rare Diseases ,Neurosciences ,Sleep Research ,Huntington's Disease ,Neurodegenerative ,Brain Disorders ,Behavioral and Social Science ,Neurological ,Medicinal and Biomolecular Chemistry ,Pharmacology and Pharmaceutical Sciences - Abstract
Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder characterized by motor as well as nonmotor symptoms for which there is currently no cure. The Q175 mouse model of HD recapitulates many of the symptoms identified in HD patients including disruptions of the sleep/wake cycle. In this study, we sought to determine if the daily administration of the histamine-3 receptor (H3R) antagonist/inverse agonist 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) would improve nonmotor symptoms in the Q175 line. This class of drugs acts on autoreceptors found at histaminergic synapses and results in increased levels of histamine (HA). HA is a neuromodulator whose levels vary with a daily rhythm with peak release during the active cycle and relatively lower levels during sleep. H3Rs are widely expressed in brain regions involved in cognitive processes and activation of these receptors promotes wakefulness. We administered GSK189254 nightly to homozygote and heterozygote Q175 mice for 4 weeks and confirmed that the plasma levels of the drug were elevated to a therapeutic range. We demonstrate that daily treatment with GSK189254 improved several behavioral measures in the Q175 mice including strengthening activity rhythms, cognitive performance and mood as measured by the tail suspension test. The treatment also reduced inappropriate activity during the normal sleep time. The drug treatment did not alter motor performance and coordination as measured by the challenging beam test. Our findings suggest that drugs targeting the H3R system may show benefits as cognitive enhancers in the management of HD.
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- 2017
29. Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease.
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Cutler, Tamara S, Park, Saemi, Loh, Dawn H, Jordan, Maria C, Yokota, Tomohiro, Roos, Kenneth P, Ghiani, Cristina A, and Colwell, Christopher S
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Heart ,Autonomic Nervous System ,Animals ,Mice ,Inbred C57BL ,Mice ,Huntington Disease ,Stroke Volume ,Body Temperature ,Circadian Rhythm ,Blood Pressure ,Heart Rate ,Baroreflex ,Mutation ,Male ,Huntingtin Protein ,Autonomic nervous system ,Huntington's disease ,baroreceptor reflex ,cardiovascular function ,circadian rhythms ,core body temperature ,echocardiograms ,electrocardiograms ,fibrosis ,heart rate variability ,radio telemetry ,Inbred C57BL ,Huntingtons disease ,Physiology ,Clinical Sciences ,Medical Physiology - Abstract
Cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with Huntington's disease (HD). Preclinical research requires mouse models that recapitulate disease symptoms and the Q175 knock-in model offers a number of advantages but potential autonomic dysfunction has not been explored. In this study, we sought to test the dual hypotheses that cardiovascular dysautonomia can be detected early in disease progression in the Q175 model and that this dysfunction varies with the daily cycle. Using radiotelemetry implants, we observed a significant reduction in the diurnal and circadian activity rhythms in the Q175 mutants at the youngest ages. By middle age, the autonomically driven rhythms in core body temperature were highly compromised, and the Q175 mutants exhibited striking episodes of hypothermia that increased in frequency with mutant huntingtin gene dosage. In addition, Q175 mutants showed higher resting heart rate (HR) during sleep and greatly reduced correlation between activity and HR HR variability was reduced in the mutants in both time and frequency domains, providing more evidence of autonomic dysfunction. Measurement of the baroreceptor reflex revealed that the Q175 mutant could not appropriately increase HR in response to a pharmacologically induced decrease in blood pressure. Echocardiograms showed reduced ventricular mass and ejection fraction in mutant hearts. Finally, cardiac histopathology revealed localized points of fibrosis resembling those caused by myocardial infarction. Thus, the Q175 mouse model of HD exhibits cardiovascular dysautonomia similar to that seen in HD patients with prominent sympathetic dysfunction during the resting phase of the activity rhythm.
- Published
- 2017
30. A human microprotein that interacts with the mRNA decapping complex
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D'Lima, Nadia G, Ma, Jiao, Winkler, Lauren, Chu, Qian, Loh, Ken H, Corpuz, Elizabeth O, Budnik, Bogdan A, Lykke-Andersen, Jens, Saghatelian, Alan, and Slavoff, Sarah A
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Analytical Chemistry ,Chemical Sciences ,Animals ,COS Cells ,Carrier Proteins ,Cells ,Cultured ,Chlorocebus aethiops ,Endoribonucleases ,Humans ,RNA Caps ,RNA ,Messenger ,Medicinal and Biomolecular Chemistry ,Biochemistry and Cell Biology ,Biochemistry & Molecular Biology ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - Abstract
Proteomic detection of non-annotated microproteins indicates the translation of hundreds of small open reading frames (smORFs) in human cells, but whether these microproteins are functional or not is unknown. Here, we report the discovery and characterization of a 7-kDa human microprotein we named non-annotated P-body dissociating polypeptide (NoBody). NoBody interacts with mRNA decapping proteins, which remove the 5' cap from mRNAs to promote 5'-to-3' decay. Decapping proteins participate in mRNA turnover and nonsense-mediated decay (NMD). NoBody localizes to mRNA-decay-associated RNA-protein granules called P-bodies. Modulation of NoBody levels reveals that its abundance is anticorrelated with cellular P-body numbers and alters the steady-state levels of a cellular NMD substrate. These results implicate NoBody as a novel component of the mRNA decapping complex and demonstrate potential functionality of a newly discovered microprotein.
- Published
- 2017
31. Blue light therapy improves circadian dysfunction as well as motor symptoms in two mouse models of Huntington's disease.
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Wang, Huei-Bin, Whittaker, Daniel S, Truong, Danny, Mulji, Aly K, Ghiani, Cristina A, Loh, Dawn H, and Colwell, Christopher S
- Subjects
BACHD ,BACHD ,bacterial artificial chromosome mouse model of HD ,Blue light therapy ,Circadian rhythms ,HD ,Huntington's disease ,HTT ,Huntingtin protein ,Htt ,huntingtin gene ,Huntington's disease ,KI ,knock in ,Photic therapy ,Q175 ,SCN ,suprachiasmatic nucleus ,UCLA ,University of California ,Los Angeles ,ZT ,Zeitgeber time ,ipRGCs ,intrinsically photoreceptive retinal ganglion cells ,blue light therapy ,circadian rhythms ,photic therapy - Abstract
Patients with Huntington's disease (HD) exhibit movement disorders, psychiatric disturbance and cognitive impairments as the disease progresses. Abnormal sleep/wake cycles are common among HD patients with reports of delayed sleep onset, fatigue during the day, and a delayed pattern of melatonin secretion all of which suggest circadian dysfunction. Mouse models of HD confirm disrupted circadian rhythms with pathophysiology found in the central circadian clock (suprachiasmatic nucleus). Importantly, circadian dysfunction manifests early in disease, even before the classic motor symptoms, in both patients and mouse models. Therefore, we hypothesize that the circadian dysfunction may interact with the disease pathology and exacerbate the HD symptoms. If correct, early intervention may benefit patients and delay disease progression. One test of this hypothesis is to determine whether light therapy designed to strengthen this intrinsic timing system can delay the disease progression in mouse models. Therefore, we determined the impact of blue wavelength-enriched light on two HD models: the BACHD and Q175 mice. Both models received 6 h of blue-light at the beginning of their daily light cycle for 3 months. After treatment, both genotypes showed improvements in their locomotor activity rhythm without significant change to their sleep behavior. Critically, treated mice of both lines exhibited improved motor performance compared to untreated controls. Focusing on the Q175 genotype, we sought to determine whether the treatment altered signaling pathways in brain regions known to be impacted by HD using NanoString gene expression assays. We found that the expression of several HD relevant markers was altered in the striatum and cortex of the treated mice. Our study demonstrates that strengthening the circadian system can delay the progression of HD in pre-clinical models. This work suggests that lighting conditions should be considered when managing treatment of HD and other neurodegenerative disorders.
- Published
- 2017
32. Naloxone Facilitates Contextual Learning and Memory in a Receptor-Independent and Tet1-Dependent Manner
- Author
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Meng, Fei, Li, Yuan, Sun, Hao, Li, Changpeng, Li, Qian, Law, Ping-Yee, Loh, Horace H., Liang, Lining, and Zheng, Hui
- Published
- 2021
- Full Text
- View/download PDF
33. Implementation of B'More Healthy Communities for Kids: Process Evaluation of a Multi-Level, Multi-Component Obesity Prevention Intervention
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Ruggiero, C. F., Poirier, L., Trude, A. C. B., Yang, T., Schwendler, T., Gunen, B., Loh, I. H., Perepezko, K., Nam, C. S., Sato, P., and Gittelsohn, J.
- Abstract
B'More Healthy Communities for Kids was a multi-level, multi-component obesity prevention intervention to improve access, demand and consumption of healthier foods and beverages in 28 low-income neighborhoods in Baltimore City, MD. Process evaluation assesses the implementation of an intervention and monitor progress. To the best of our knowledge, little detailed process data from multi-level obesity prevention trials have been published. Implementation of each intervention component (wholesaler, recreation center, carryout restaurant, corner store, policy and social media/text messaging) was classified as high, medium or low according to set standards. The wholesaler component achieved high implementation for reach, dose delivered and fidelity. Recreation center and carryout restaurant components achieved medium reach, dose delivered and fidelity. Corner stores achieved medium reach and dose delivered and high fidelity. The policy component achieved high reach and medium dose delivered and fidelity. Social media/text messaging achieved medium reach and high dose delivered and fidelity. Overall, study reach and dose delivered achieved a high implementation level, whereas fidelity achieved a medium level. Varying levels of implementation may have balanced the performance of an intervention component for each process evaluation construct. This detailed process evaluation of the B'More Healthy Communities for Kids allowed the assessment of implementation successes, failures and challenges of each intervention component.
- Published
- 2018
- Full Text
- View/download PDF
34. Proteomic Analysis of Unbounded Cellular Compartments: Synaptic Clefts
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Loh, Ken H, Stawski, Philipp S, Draycott, Austin S, Udeshi, Namrata D, Lehrman, Emily K, Wilton, Daniel K, Svinkina, Tanya, Deerinck, Thomas J, Ellisman, Mark H, Stevens, Beth, Carr, Steven A, and Ting, Alice Y
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Neurosciences ,Biological Sciences ,Biotechnology ,Underpinning research ,1.1 Normal biological development and functioning ,Neurological ,Animals ,Antigens ,CD ,Cell Adhesion Molecules ,Neuronal ,GABAergic Neurons ,Glutamic Acid ,HEK293 Cells ,Humans ,Immunoglobulins ,Membrane Glycoproteins ,Mice ,Nerve Tissue Proteins ,Neural Cell Adhesion Molecules ,Peroxidase ,Proteome ,Proteomics ,Rats ,Receptors ,GABA ,Recombinant Fusion Proteins ,Synaptic Membranes ,Thalamus ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Cellular compartments that cannot be biochemically isolated are challenging to characterize. Here we demonstrate the proteomic characterization of the synaptic clefts that exist at both excitatory and inhibitory synapses. Normal brain function relies on the careful balance of these opposing neural connections, and understanding how this balance is achieved relies on knowledge of their protein compositions. Using a spatially restricted enzymatic tagging strategy, we mapped the proteomes of two of the most common excitatory and inhibitory synaptic clefts in living neurons. These proteomes reveal dozens of synaptic candidates and assign numerous known synaptic proteins to a specific cleft type. The molecular differentiation of each cleft allowed us to identify Mdga2 as a potential specificity factor influencing Neuroligin-2's recruitment of presynaptic neurotransmitters at inhibitory synapses.
- Published
- 2016
35. Sex Differences in Circadian Dysfunction in the BACHD Mouse Model of Huntington's Disease.
- Author
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Kuljis, Dika A, Gad, Laura, Loh, Dawn H, MacDowell Kaswan, Zoë, Hitchcock, Olivia N, Ghiani, Cristina A, and Colwell, Christopher S
- Subjects
Suprachiasmatic Nucleus ,Chromosomes ,Artificial ,Bacterial ,Animals ,Mice ,Transgenic ,Humans ,Mice ,Huntington Disease ,Disease Models ,Animal ,Disease Progression ,Vasoactive Intestinal Peptide ,Rotarod Performance Test ,Motor Activity ,Sex Factors ,Gene Expression ,Circadian Rhythm ,Founder Effect ,Time Factors ,Female ,Male ,Arginine Vasopressin ,General Science & Technology - Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies indicate there may be sex differences in disease progression. One of the early symptoms of HD is disruptions in the circadian timing system, but it is currently unknown whether sex is a factor in these alterations. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s) and designing early intervention strategies, we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD) to examine whether sex differences in circadian behavioral rhythms are detectable in an animal model of the disease. Similar to BACHD males, BACHD females display circadian disruptions at both 3 and 6 months of age; however, deficits to BACHD female mouse activity levels, rhythm precision, and behavioral fragmentation are either delayed or less severe relative to males. These sex differences are associated with a smaller suprachiasmatic nucleus (SCN) in BACHD male mice at age of symptom onset (3 months), but are not associated with sex-specific differences in SCN daytime electrical activity deficits, or peptide expression (arginine vasopressin, vasoactive intestinal peptide) within the SCN. Notably, BACHD females exhibited delayed motor coordination deficits, as measured using rotarod and challenge beam. These findings suggest a sex specific factor plays a role both in non-motor and motor symptom progression for the BACHD mouse.
- Published
- 2016
36. Misaligned feeding impairs memories.
- Author
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Loh, Dawn H, Jami, Shekib A, Flores, Richard E, Truong, Danny, Ghiani, Cristina A, O'Dell, Thomas J, and Colwell, Christopher S
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Hippocampus ,Suprachiasmatic Nucleus ,Animals ,Mice ,Feeding Methods ,Feeding Behavior ,Memory ,Circadian Rhythm ,CREB ,circadian rhythms ,hippocampus ,learning and memory ,mouse ,neuroscience ,Sleep Research ,Neurosciences ,Mental Health ,Behavioral and Social Science ,Basic Behavioral and Social Science ,Biochemistry and Cell Biology - Abstract
Robust sleep/wake rhythms are important for health and cognitive function. Unfortunately, many people are living in an environment where their circadian system is challenged by inappropriate meal- or work-times. Here we scheduled food access to the sleep time and examined the impact on learning and memory in mice. Under these conditions, we demonstrate that the molecular clock in the master pacemaker, the suprachiasmatic nucleus (SCN), is unaltered while the molecular clock in the hippocampus is synchronized by the timing of food availability. This chronic circadian misalignment causes reduced hippocampal long term potentiation and total CREB expression. Importantly this mis-timed feeding resulted in dramatic deficits in hippocampal-dependent learning and memory. Our findings suggest that the timing of meals have far-reaching effects on hippocampal physiology and learned behaviour.
- Published
- 2015
37. Proteins in DNA methylation and their role in neural stem cell proliferation and differentiation
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Sun, Jiaqi, Yang, Junzheng, Miao, Xiaoli, Loh, Horace H., Pei, Duanqing, and Zheng, Hui
- Published
- 2021
- Full Text
- View/download PDF
38. Loss of PRC2 subunits primes lineage choice during exit of pluripotency
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Loh, Chet H., van Genesen, Siebe, Perino, Matteo, Bark, Magnus R., and Veenstra, Gert Jan C.
- Published
- 2021
- Full Text
- View/download PDF
39. Sex differences in diurnal rhythms of food intake in mice caused by gonadal hormones and complement of sex chromosomes.
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Chen, Xuqi, Wang, Lixin, Loh, Dawn H, Colwell, Christopher S, Taché, Yvette, Reue, Karen, and Arnold, Arthur P
- Subjects
Sex Chromosomes ,Animals ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Mice ,Body Weight ,Gonadal Hormones ,Sex Factors ,Body Composition ,Circadian Rhythm ,Sex Characteristics ,Eating ,Genotype ,Female ,Male ,Adiposity ,Body composition ,Circadian rhythm ,Estradiol ,Food intake ,Four Core Genotypes ,Night eating ,Obesity ,Sex chromosomes ,Sex differences ,Testosterone ,Behavioral and Social Science ,Basic Behavioral and Social Science ,Nutrition ,Metabolic and endocrine ,Biological Sciences ,Medical and Health Sciences ,Behavioral Science & Comparative Psychology - Abstract
We measured diurnal rhythms of food intake, as well as body weight and composition, while varying three major classes of sex-biasing factors: activational and organizational effects of gonadal hormones, and sex chromosome complement (SCC). Four Core Genotypes (FCG) mice, comprising XX and XY gonadal males and XX and XY gonadal females, were either gonad-intact or gonadectomized (GDX) as adults (2.5months); food intake was measured second-by-second for 7days starting 5weeks later, and body weight and composition were measured for 22weeks thereafter. Gonadal males weighed more than females. GDX increased body weight/fat of gonadal females, but increased body fat and reduced body weight of males. After GDX, XX mice had greater body weight and more fat than XY mice. In gonad-intact mice, males had greater total food intake and more meals than females during the dark phase, but females had more food intake and meals and larger meals than males during the light phase. GDX reduced overall food intake irrespective of gonad type or SCC, and eliminated differences in feeding between groups with different gonads. Diurnal phase of feeding was influenced by all three sex-biasing variables. Gonad-intact females had earlier onset and acrophase (peak) of feeding relative to males. GDX caused a phase-advance of feeding, especially in XX mice, leading to an earlier onset of feeding in GDX XX vs. XY mice, but earlier acrophase in GDX males relative to females. Gonadal hormones and SCC interact in the control of diurnal rhythms of food intake.
- Published
- 2015
40. Targeting Transmission Pathways for Emerging Zoonotic Disease Surveillance and Control
- Author
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Loh, Elizabeth H, Zambrana-Torrelio, Carlos, Olival, Kevin J, Bogich, Tiffany L, Johnson, Christine K, Mazet, Jonna AK, Karesh, William, and Daszak, Peter
- Subjects
2.4 Surveillance and distribution ,Aetiology ,Infection ,Good Health and Well Being ,Agriculture ,Animals ,Communicable Diseases ,Emerging ,Demography ,Disease Reservoirs ,Environment ,Epidemiological Monitoring ,Humans ,Public Health ,Travel ,Zoonoses ,Surveillance ,Transmission routes ,Pathway ,Direct contact ,Vector-borne ,Virus ,Zoonosis ,Public Health and Health Services ,Tropical Medicine - Abstract
We used literature searches and a database of all reported emerging infectious diseases (EIDs) to analyze the most important transmission pathways (e.g., vector-borne, aerosol droplet transmitted) for emerging zoonoses. Our results suggest that at the broad scale, the likelihood of transmission occurring through any one pathway is approximately equal. However, the major transmission pathways for zoonoses differ widely according to the specific underlying drivers of EID events (e.g., land-use change, agricultural intensification). These results can be used to develop better targeting of surveillance for, and more effective control of newly emerged zoonoses in regions under different underlying pressures that drive disease emergence.
- Published
- 2015
41. Short Circuiting the Circadian System with a New Generation of Precision Tools
- Author
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Loh, Dawn H, Kudo, Takashi, and Colwell, Christopher S
- Subjects
Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Genetics ,Sleep Research ,Good Health and Well Being ,ARNTL Transcription Factors ,Animals ,Arginine Vasopressin ,Circadian Clocks ,Circadian Rhythm ,Interneurons ,Neurons ,Neuropeptides ,Suprachiasmatic Nucleus ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Circadian behavior in mammals is coordinated by neurons within the suprachiasmatic nucleus (SCN). In this issue, Lee et al. (2015) and Mieda et al. (2015) applied state-of-the-art genetic tools to dissect the microcircuits within the SCN generating circadian rhythmic behavior.
- Published
- 2015
42. Measurement of a reaction-diffusion crossover in exciton-exciton recombination inside carbon nanotubes using femtosecond optical absorption
- Author
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Allam, J., Sajjad, M. T., Sutton, R., Litvinenko, K., Wang, Z., Siddique, S., Yang, Q-H., Loh, W. H., and Brown, T.
- Subjects
Condensed Matter - Statistical Mechanics ,Condensed Matter - Mesoscale and Nanoscale Physics - Abstract
Exciton-exciton recombination in isolated semiconducting single-walled carbon nanotubes was studied using femtosecond transient absorption. Under sufficient excitation to saturate the optical absorption, we observed an abrupt transition between reaction- and diffusion- limited kinetics, arising from reactions between incoherent localized excitons with a finite probability of ~ 0.2 per encounter. This represents the first experimental observation of a crossover between classical and critical kinetics in a 1D coalescing random walk, which is a paradigm for the study of non- equilibrium systems., Comment: Accepted for Physical Review Letters. Title changed, and "exciton fusion" replaced by "exciton-exciton recombination". Present address of Prof Tom Brown added. 12 pages plus 3 figures
- Published
- 2013
- Full Text
- View/download PDF
43. Development and Validation of a Tool to Screen for Cognitive Frailty Among Community-Dwelling Elders
- Author
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Tseng, S.-H., Liu, L.-K., Peng, Li-Ning, Wang, P.-N., Loh, C.-H., and Chen, Liang-Kung
- Published
- 2019
- Full Text
- View/download PDF
44. Correction: Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease
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Yu, Yizhou, Fedele, Giorgio, Celardo, Ivana, Loh, Samantha H. Y., and Martins, L. Miguel
- Published
- 2021
- Full Text
- View/download PDF
45. Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease
- Author
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Yu, Yizhou, Fedele, Giorgio, Celardo, Ivana, Loh, Samantha H. Y., and Martins, L. Miguel
- Published
- 2021
- Full Text
- View/download PDF
46. Circadian dysfunction in response to in vivo treatment with the mitochondrial toxin 3-nitropropionic acid.
- Author
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Kudo, Takashi, Loh, Dawn H, Tahara, Yu, Truong, Danny, Hernández-Echeagaray, Elizabeth, and Colwell, Christopher S
- Subjects
Suprachiasmatic Nucleus ,Mitochondria ,Animals ,Mice ,Inbred C57BL ,Mice ,Huntington Disease ,Propionates ,Nitro Compounds ,Convulsants ,Patch-Clamp Techniques ,Sleep ,Male ,Gene Knock-In Techniques ,Period Circadian Proteins ,Circadian Clocks ,circadian ,clock ,suprachiasmatic ,Inbred C57BL ,Neurosciences - Abstract
Sleep disorders are common in neurodegenerative diseases including Huntington's disease (HD) and develop early in the disease process. Mitochondrial alterations are believed to play a critical role in the pathophysiology of neurodegenerative diseases. In the present study, we evaluated the circadian system of mice after inhibiting mitochondrial complex II of the respiratory chain with the toxin 3-nitropropionic acid (3-NP). We found that a subset of mice treated with low doses of 3-NP exhibited severe circadian deficit in behavior. The temporal patterning of sleep behavior is also disrupted in some mice with evidence of difficulty in the initiation of sleep behavior. Using the open field test during the normal sleep phase, we found that the 3-NP-treated mice were hyperactive. The molecular clockwork responsible for the generation of circadian rhythms as measured by PER2::LUCIFERASE was disrupted in a subset of mice. Within the SCN, the 3-NP treatment resulted in a reduction in daytime firing rate in the subset of mice which had a behavioral deficit. Anatomically, we confirmed that all of the treated mice showed evidence for cell loss within the striatum but we did not see evidence for gross SCN pathology. Together, the data demonstrates that chronic treatment with low doses of the mitochondrial toxin 3-NP produced circadian deficits in a subset of treated mice. This work does raise the possibility that the neural damage produced by mitochondrial dysfunction can contribute to the sleep/circadian dysfunction seen so commonly in neurodegenerative diseases.
- Published
- 2014
47. Circadian Dysfunction in Response to in Vivo Treatment with the Mitochondrial Toxin 3-Nitropropionic Acid
- Author
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Kudo, Takashi, Loh, Dawn H, Tahara, Yu, Truong, Danny, Hernández-Echeagaray, Elizabeth, and Colwell, Christopher S
- Subjects
Neurodegenerative ,Brain Disorders ,Sleep Research ,Huntington's Disease ,Neurosciences ,Rare Diseases ,Neurological ,Animals ,Circadian Clocks ,Convulsants ,Gene Knock-In Techniques ,Huntington Disease ,Male ,Mice ,Mice ,Inbred C57BL ,Mitochondria ,Nitro Compounds ,Patch-Clamp Techniques ,Period Circadian Proteins ,Propionates ,Sleep ,Suprachiasmatic Nucleus ,circadian ,clock ,suprachiasmatic - Abstract
Sleep disorders are common in neurodegenerative diseases including Huntington's disease (HD) and develop early in the disease process. Mitochondrial alterations are believed to play a critical role in the pathophysiology of neurodegenerative diseases. In the present study, we evaluated the circadian system of mice after inhibiting mitochondrial complex II of the respiratory chain with the toxin 3-nitropropionic acid (3-NP). We found that a subset of mice treated with low doses of 3-NP exhibited severe circadian deficit in behavior. The temporal patterning of sleep behavior is also disrupted in some mice with evidence of difficulty in the initiation of sleep behavior. Using the open field test during the normal sleep phase, we found that the 3-NP-treated mice were hyperactive. The molecular clockwork responsible for the generation of circadian rhythms as measured by PER2::LUCIFERASE was disrupted in a subset of mice. Within the SCN, the 3-NP treatment resulted in a reduction in daytime firing rate in the subset of mice which had a behavioral deficit. Anatomically, we confirmed that all of the treated mice showed evidence for cell loss within the striatum but we did not see evidence for gross SCN pathology. Together, the data demonstrates that chronic treatment with low doses of the mitochondrial toxin 3-NP produced circadian deficits in a subset of treated mice. This work does raise the possibility that the neural damage produced by mitochondrial dysfunction can contribute to the sleep/circadian dysfunction seen so commonly in neurodegenerative diseases.
- Published
- 2013
48. The Q175 mouse model of Huntington's disease shows gene dosage- and age-related decline in circadian rhythms of activity and sleep.
- Author
-
Loh, Dawn H, Kudo, Takashi, Truong, Danny, Wu, Yingfei, and Colwell, Christopher S
- Subjects
Animals ,Mice ,Transgenic ,Humans ,Mice ,Huntington Disease ,Disease Models ,Animal ,Nerve Tissue Proteins ,Motor Activity ,Sleep ,Age Factors ,Circadian Rhythm ,Genotype ,Gene Dosage ,Mutation ,Alleles ,Male ,Huntingtin Protein ,Disease Models ,Animal ,Transgenic ,General Science & Technology - Abstract
Sleep and circadian disruptions are commonly reported by patients with neurodegenerative diseases, suggesting these may be an endophenotype of the disorders. Several mouse models of Huntington's disease (HD) that recapitulate the disease progression and motor dysfunction of HD also exhibit sleep and circadian rhythm disruption. Of these, the strongest effects are observed in the transgenic models with multiple copies of mutant huntingtin gene. For developing treatments of the human disease, knock-in (KI) models offer advantages of genetic precision of the insertion and control of mutation copy number. Therefore, we assayed locomotor activity and immobility-defined sleep in a new model of HD with an expansion of the KI repeats (Q175). We found evidence for gene dose- and age-dependent circadian disruption in the behavior of the Q175 line. We did not see evidence for loss of cells or disruption of the molecular oscillator in the master pacemaker, the suprachiasmatic nucleus (SCN). The combination of the precise genetic targeting in the Q175 model and the observed sleep and circadian disruptions make it tractable to study the interaction of the underlying pathology of HD and the mechanisms by which the disruptions occur.
- Published
- 2013
49. Ecology of zoonoses: natural and unnatural histories
- Author
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Karesh, William B, Dobson, Andy, Lloyd-Smith, James O, Lubroth, Juan, Dixon, Matthew A, Bennett, Malcolm, Aldrich, Stephen, Harrington, Todd, Formenty, Pierre, Loh, Elizabeth H, Machalaba, Catherine C, Thomas, Mathew Jason, and Heymann, David L
- Subjects
Prevention ,Emerging Infectious Diseases ,Biotechnology ,Infectious Diseases ,Vaccine Related ,Biodefense ,Aetiology ,2.4 Surveillance and distribution ,Infection ,Good Health and Well Being ,Animals ,Animals ,Domestic ,Animals ,Wild ,Communicable Diseases ,Emerging ,Drug Resistance ,Microbial ,Ecosystem ,Extraction and Processing Industry ,Food Supply ,HIV Infections ,Humans ,Influenza A Virus ,H5N1 Subtype ,Influenza ,Human ,Pandemics ,Risk Factors ,Zoonoses ,Medical and Health Sciences ,General & Internal Medicine - Abstract
More than 60% of human infectious diseases are caused by pathogens shared with wild or domestic animals. Zoonotic disease organisms include those that are endemic in human populations or enzootic in animal populations with frequent cross-species transmission to people. Some of these diseases have only emerged recently. Together, these organisms are responsible for a substantial burden of disease, with endemic and enzootic zoonoses causing about a billion cases of illness in people and millions of deaths every year. Emerging zoonoses are a growing threat to global health and have caused hundreds of billions of US dollars of economic damage in the past 20 years. We aimed to review how zoonotic diseases result from natural pathogen ecology, and how other circumstances, such as animal production, extraction of natural resources, and antimicrobial application change the dynamics of disease exposure to human beings. In view of present anthropogenic trends, a more effective approach to zoonotic disease prevention and control will require a broad view of medicine that emphasises evidence-based decision making and integrates ecological and evolutionary principles of animal, human, and environmental factors. This broad view is essential for the successful development of policies and practices that reduce probability of future zoonotic emergence, targeted surveillance and strategic prevention, and engagement of partners outside the medical community to help improve health outcomes and reduce disease threats.
- Published
- 2012
50. Rapid changes in the light/dark cycle disrupt memory of conditioned fear in mice.
- Author
-
Loh, Dawn H, Navarro, Juliana, Hagopian, Arkady, Wang, Louisa M, Deboer, Tom, and Colwell, Christopher S
- Subjects
Animals ,Mice ,Inbred C57BL ,Humans ,Mice ,Models ,Animal ,Fear ,Memory ,Circadian Rhythm ,Light ,Photoperiod ,Male ,Inbred C57BL ,Models ,Animal ,General Science & Technology - Abstract
BackgroundCircadian rhythms govern many aspects of physiology and behavior including cognitive processes. Components of neural circuits involved in learning and memory, e.g., the amygdala and the hippocampus, exhibit circadian rhythms in gene expression and signaling pathways. The functional significance of these rhythms is still not understood. In the present study, we sought to determine the impact of transiently disrupting the circadian system by shifting the light/dark (LD) cycle. Such "jet lag" treatments alter daily rhythms of gene expression that underlie circadian oscillations as well as disrupt the synchrony between the multiple oscillators found within the body.Methodology/principal findingsWe subjected adult male C57Bl/6 mice to a contextual fear conditioning protocol either before or after acute phase shifts of the LD cycle. As part of this study, we examined the impact of phase advances and phase delays, and the effects of different magnitudes of phase shifts. Under all conditions tested, we found that recall of fear conditioned behavior was specifically affected by the jet lag. We found that phase shifts potentiated the stress-evoked corticosterone response without altering baseline levels of this hormone. The jet lag treatment did not result in overall sleep deprivation, but altered the temporal distribution of sleep. Finally, we found that prior experience of jet lag helps to compensate for the reduced recall due to acute phase shifts.Conclusions/significanceAcute changes to the LD cycle affect the recall of fear-conditioned behavior. This suggests that a synchronized circadian system may be broadly important for normal cognition and that the consolidation of memories may be particularly sensitive to disruptions of circadian timing.
- Published
- 2010
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